title: Source of the elevation Ca2+ evoked by 15-HETE in pulmonary arterial myocytes.
abstract: We have previously reported that 15-hydroxyeicosatetraenoic acid (15-HETE), a metabolite of arachidonic acid by 15-lipoxygenase, causes pulmonary vasoconstriction via increasing the intracellular Ca(2+) concentration ([Ca(2+)]i). However, the multiple sources of Ca(2+) that contribute to Ca(2+) elevation during and after 15-HETE exposure have not been investigated. In the present study, pulmonary arterial ring technique and confocal laser scanning microscope were used to investigate the origin of Ca(2+). 15-HETE (1 microM) elicited an increase in [Ca(2+)]i in pulmonary artery smooth muscle cells in a time-dependent manner under both normal and hypoxic condition. The increases were composed of an initial rapid rise followed by a slow increase in the present of extracellular Ca(2+). The initial rapid phase was attenuated by inositol 1,4,5-triphosphate (IP(3)) receptor antagonist 2-aminoethoxydiphenyl borate (2-APB) and ryanodine receptor-operated Ca(2+) store depletion agent caffeine; the slow increasing phase and the constriction of pulmonary arterial ring were significantly inhibited by voltage-operated Ca(2+) channel blocker nifedipine or transient receptor potential canonical (TRPC) channel blocker La(3+), and almost completely diminished in Ca(2+)-free external solution, suggesting that the initial phase depends on intracellular Ca(2+) store and the second phase relies on extracellular Ca(2+). Interestingly, the effect of caffeine and La(3+) but not nifedipine were diminished in the present of 2-APB. Thus, these results suggest that 15-HETE mobilizes Ca(2+) signaling through: 1) Ca(2+) release immediately from Ca(2+) stores via activation of IP(3) receptor and, subsequently that of ryanodine receptor, 2) the depletion of Ca(2+) through CCE leading to the activation of TRPC, and 3) Ca(2+) entry through L-type Ca(2+) channels.
authors.affiliation: Department of Biopharmaceutical Sciences, Harbin 150081, PR China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zheng
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Tang
authors.forename: Shujun
authors.initials: S
authors.lastname: Liang
authors.forename: Lipeng
authors.initials: L
authors.lastname: Chen
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.forename: Daling
authors.initials: D
authors.lastname: Zhu
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D015687:Cell Hypoxia; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism; D050052:TRPC Cation Channels / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D020746:Calcium Channels, L-Type; D006893:Hydroxyeicosatetraenoic Acids; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019837:Ryanodine Receptor Calcium Release Channel; D050052:TRPC Cation Channels; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D002118:Calcium